Isoproterenol hydrochloride (1a), chemically identified as hydrochloride salt of 3,4-dihydroxy-α-[(isopropylamino) methyl]benzyl alcohol or 1-(3,4-dihydroxyphenyl)-2-isopropylaminoethanol is represented as given below.

Isoproterenol, an isopropyl analog of epinephrine is a non-selective β-adrenoreceptor agonist and TAAR1 agonist which exhibits f-sympathomimetic action on the beta receptors of heart, bronchi, skeletal muscle, alimentary tract etc. It is employed for the treatment of bradycardia (slow heart rate), heart block, and rarely for asthma. Isoproterenol is a potent nonselective beta-adrenergic agonist with very low affinity for alpha-adrenergic receptors.
Isoproterenol hydrochloride injection is indicated in the following conditions.
a) Mild or transient episodes of heart block that do not require electric shock or pacemaker therapy,
b) Serious episodes of heart block and Adams-Stokes attacks
c) In cardiac arrest until electric shock or pacemaker therapy is available.
d) Bronchospasm occurring during anesthesia and
e) As an adjunct to fluid and electrolyte replacement therapy
Generic version of isoproterenol hydrochloride is marketed by Nexus Pharmaceuticals Inc., while Hospira Inc. markets it under the trade name Isuprel; both of which are injectables with the strength of 0.2 mg/ml.
U.S. Pat. No. 2,308,232 discloses a process for the preparation of isoproterenol comprising reaction of 3,5-dihydroxyphenyl-ω-chloroacetophenone with excess of isopropylamine, using ethanol as solvent, followed by palladium, platinum or nickel catalyzed hydrogenation of the resulting isopropylamino acetophenone derivative to yield the desired product. The disclosed process reveals that in order to achieve the desired purity, both the ketone intermediate and final compound need to be purified through their respective salt formation followed by crystallization. This clearly indicates formation of impurities in significant proportions, thereby adversely affecting the yield and making the process industrially unviable.
AT 178353 and U.S. Pat. No. 2,715,141 disclose processes for separation of the desired enantiomcr of isoproterenol comprising treatment of the racemic mixture with d-tartaric acid. The method comprises dissolving a mixture of isoproterenol sulfate and D-tartaric acid in water and treating with barium hydroxide. Filtration of barium sulfate precipitate, concentration of the filtrate, and further resolution of the concentrate by fractional crystallization using methanol and acetone provides optically active isoproterenol.
U.S. Pat. No. 5,442,118 discloses a method for preparation of enantiopure isoproterenol comprising use of a borane reducing agent, and a chiral 1, 3, 2-oxazaborole derivative catalyst. In this method, treatment of corresponding acetophenone with HBr in DMSO, followed by reaction with water provides the arylglyoxal derivative, which, after reaction with the appropriate amine gives ketoimine derivative. Reduction of the ketoimine using the organoboranes like Me2S—BH3 in presence of said oxazaborole catalysts provides isoproterenol.
CN 107011188 discloses Friedel-Crafts reaction of catechol and glycine in the presence of zinc chloride to give 2-amino-1-(3,4-dihydroxy phenyl)ethanone, which after reaction with isopropyl chloride and catalytic hydrogenation provides isoproterenol.
It is evident from the study of prior art that conventional synthetic methods reported for isoproterenol suffer from formation of impurities in significant proportions. In these methods, undesired impurities such as impurity-A are generated during the final stage of ketone-reduction. These impurities, being structurally similar to isoproterenol, are difficult to remove during work up procedures and thus necessitate steps like chromatographic purifications or repeated crystallization procedures. This causes increase in number of procedural steps; resulting in significant yield loss and ultimately, substantially increased project cost.

To circumvent the challenge of associated impurities generated during the aforementioned reactions, some synthetic methods reported in prior art have resorted to use of highly specific intermediates like keto-imines. However, this requires use of specific reagents, adds to the number of synthetic steps and increases the project cost.
Hence, there is a need to have a cost effective, industrially applicable process which avoids use of expensive catalysts, significantly controls the formation of impurities such as impurity-A and provides isoproterenol having desired purity.
The present inventors have developed a robust and commercially viable synthetic method which avoids the short-comings in the prior art and provides isoproterenol hydrochloride (1a) conforming to regulatory specifications.